The resurgence of tuberculosis and the spread of antibiotic resistant strains of the causative agent, Mycobacterium tuberculosis, present a significant public health challenge. Tuberculosis kills nearly 2 million people each year and estimates put the worldwide population of infected individuals at nearly 2 billion. A majority of these people (90%) carries latent, asymptomatic infections that reactivate causing disease and spread of M. tuberculosis to uninfected individuals. The latent phase and the slow growth rate of M. tuberculosis limit the effectiveness of existing antibiotics. One approach to treatment of tuberculosis would be to design drugs that inhibit the establishment of the latent phase or reactivate growth under conditions allowing aggressive treatment of the infection. This application proposes that uncharacterized toxin-antitoxin systems in M. tuberculosis may play a role in the establishment and maintenance of the latent phase of infection. The experiments are designed to (i) test the hypothesis that activation of these systems induces a static metabolic state in cells and (ii) identify the molecular targets of the toxins. These studies will lay the groundwork for a thorough analysis of the molecular biology of these toxin-antitoxin systems with the goal of designing therapeutic approaches to the treatment of latent M. tuberculosis infections. PUBLIC HEALTH RELEVANCE: Tuberculosis kills nearly 2 million people each year and estimates put the worldwide population of infected individuals at nearly 2 billion. A majority of these people (90%) carry latent, asymptomatic infections that reactivate causing disease and spread of M. tuberculosis to uninfected individuals. The goal of this research is to characterize a set of M. tuberculosis proteins that may play a role in latency and to lay the groundwork for the design of new therapeutic approaches to the treatment of latent M. tuberculosis infections.